A Pan-Cancer Landscape Analysis Reveals a Subset of Endometrial Stromal and Pediatric Tumors Defined by Internal Tandem Duplications of BCOR

Juckett, Luke; Lin, Douglas I.; Madison, Russell; Ross, Jeffrey S.; Schrock, Alexa B.; Ali, Siraj M.

doi:10.1159/000493322

Cited by 37 publications

(15 citation statements)

References 14 publications

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“…More recently, however, this same genetic change has been found in PMMTI [ 10 , 12 , 13 , 14 ], providing a pathogenetic link between CCSK and PMMTI, and giving rise to the concept that PMMTI is the soft tissue counterpart of CCSK. BCOR ITDs have also been reported in high‐grade endometrial stromal sarcoma of the adult uterus [ 31 ] and one type of embryonal tumour of the central nervous system, previously referred to as ‘primitive neuroectodermal tumour’ but now renamed as ‘central nervous system embryonal tumour with BCOR internal tandem duplication’ [ 32 , 33 ]. The novel splicing phenomenon occurring within the context of an unusually long ITD in our cases of CCSK and PMMTI has not been described to date in these other tumours.…”

Section: Discussionmentioning

confidence: 99%

Paediatric BCOR‐associated sarcomas with a novel long spliced internal tandem duplication of BCOR exon 15

Goh

Kuick

Sugiura

et al. 2022

The Journal of Pathology CR

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Clear cell sarcoma of the kidney (CCSK) and primitive myxoid mesenchymal tumour of infancy (PMMTI) are paediatric sarcomas that most commonly harbour internal tandem duplications (ITDs) of exon 15 of the BCOR gene, in the range of 87–114 base pairs (bp). Some cases, instead, have BCOR‐CCNB3 or YWHAE‐NUTM2 gene fusions. About 10% of cases lack any of these genetic alterations when tested by standard methods. Two cases of CCSK and one PMMTI lacking the aforementioned mutations were analysed using Archer FusionPlex technology. Two related BCOR exon 15 RNA transcripts with ITDs of lengths 388 and 96 bp were detected in each case; only the 388 bp transcript was identified when genomic DNA was sequenced. In silico analysis of this transcript revealed acceptor and donor splice sites indicating that, at the RNA level, the 388‐bp transcript was likely spliced to form the 96‐bp transcript. The results were confirmed by Sanger sequencing using primers targeting the ITD breakpoint. This novel and unusually long ITD segment is difficult to identify by DNA sequencing using typical primer design strategies flanking entire duplicated segments because it exceeds the typical read lengths of most sequencing platforms as well as the usual fragment lengths obtained from formalin‐fixed paraffin‐embedded material. As diagnosis of CCSK and PMMTI may be challenging by morphology and immunohistochemistry alone, it is important to identify mutations in these cases. Knowledge of this novel BCOR ITD is important in relation to primer design for detection by sequencing, and using RNA versus DNA for sequencing.

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Section: Discussionmentioning

confidence: 99%

Paediatric BCOR‐associated sarcomas with a novel long spliced internal tandem duplication of BCOR exon 15

Goh

Kuick

Sugiura

et al. 2022

The Journal of Pathology CR

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“…Morphological spectra vary according to genetic abnormalities. Recently, another subtype of a ZC3H7B-BCOR gene fusion-induced HG-ESS was discovered in new studies ( 11 – 14 ). Significant genetic alterations of HG-ESS show distinct characters and patterns histologically and mechanistically.…”

Section: Hg-essmentioning

confidence: 99%

“…We aim to enlighten the complicity of BCOR-ESS via the viewpoint of genetic alterations and the tumor microenvironment (TME) formations. (11)(12)(13)(14). Significant genetic alterations of HG-ESS show distinct characters and patterns histologically and mechanistically.…”

Section: Introductionmentioning

confidence: 99%

High-Grade Endometrial Stromal Sarcoma: Molecular Alterations and Potential Immunotherapeutic Strategies

Kim

Sung

et al. 2022

Front. Immunol.

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Endometrial stromal tumor (EST) is an uncommon and unusual mesenchymal tumor of the uterus characterized by multicolored histopathological, immunohistochemical, and molecular features. The morphology of ESTs is similar to normal endometrial stromal cells during the proliferative phase of the menstrual cycle. ESTs were first classified into benign and malignant based on the number of mitotic cells. However, recently WHO has divided ESTs into four categories: endometrial stromal nodules (ESN), undifferentiated uterine sarcoma (UUS), low-grade endometrial stromal sarcoma (LG-ESS), and high-grade endometrial stromal sarcoma (HG-ESS). HG-ESS is the most malignant of these categories, with poor clinical outcomes compared to other types. With advances in molecular biology, ESTs have been further classified with morphological identification. ESTs, including HG-ESS, is a relatively rare type of cancer, and the therapeutics are not being developed compared to other cancers. However, considering the tumor microenvironment of usual stromal cancers, the advance of immunotherapy shows auspicious outcomes reported in many different stromal tumors and non-identified uterine cancers. These studies show the high possibility of successful immunotherapy in HG-ESS patients in the future. In this review, we are discussing the background of ESTs and the BCOR and the development of HG-ESS by mutations of BCOR or other related genes. Among the gene mutations of HG-ESSs, BCOR shows the most common mutations in different ways. In current tumor therapies, immunotherapy is one of the most effective therapeutic approaches. In order to connect immunotherapy with HG-ESS, the understanding of tumor microenvironment (TME) is required. The TME of HG-ESS shows the mixture of tumor cells, vessels, immune cells and non-malignant stromal cells. Macrophages, neutrophils, dendritic cells and natural killer cells lose their expected functions, but rather show pro-tumoral functions by the matricellular proteins, extracellular matrix and other complicated environment in TME. In order to overcome the current therapeutic limitations of HG-ESS, immunotherapies should be considered in addition to the current surgical strategies. Checkpoint inhibitors, cytokine-based immunotherapies, immune cell therapies are good candidates to be considered as they show promising results in other stromal cancers and uterine cancers, while less studied because of the rarity of ESTs. Based on the advance of knowledge of immune therapies in HG-ESS, the new strategies can also be applied to the current therapies and also in other ESTs.

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“…Translocations or chromosomal rearrangements, involving fusion proteins have also been implicated in PRCs mechanisms. Fusions such as KDM2B-CREBBP [ 158 ], ZC3H7-BCOR [ 79 , 155 , 156 , 159 , 160 ], JAZF1-BCORL1 [ 79 , 91 , 161 ], EPC1-BCOR [ 72 , 95 ], LPP-BCOR [ 72 ] and BCOR internal tandem duplications ( BCOR-ITD ) are frequently found in ESS, and have recently been also found in LMS samples [ 80 , 160 , 162 , 163 ]. Additionally, gene fusion such as MBTD1-CXorf67 [ 79 , 91 , 151 , 164 ], MBTD1-EZHIP [ 90 ] and MBTD1-PHF1 in ESS are found as products of PRC1-associated protein [ 152 ].…”

Section: Genetics and Epigenetics Mechanisms In Lms And Essmentioning

confidence: 99%

Epigenetic Features in Uterine Leiomyosarcoma and Endometrial Stromal Sarcomas: An Overview of the Literature

et al. 2022

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There is a consensus that epigenetic alterations play a key role in cancer initiation and its biology. Studies evaluating the modification in the DNA methylation and chromatin remodeling patterns, as well as gene regulation profile by non-coding RNAs (ncRNAs) have led to the development of novel therapeutic approaches to treat several tumor types. Indeed, despite clinical and translational challenges, combinatorial therapies employing agents targeting epigenetic modifications with conventional approaches have shown encouraging results. However, for rare neoplasia such as uterine leiomyosarcomas (LMS) and endometrial stromal sarcomas (ESS), treatment options are still limited. LMS has high chromosomal instability and molecular derangements, while ESS can present a specific gene fusion signature. Although they are the most frequent types of “pure” uterine sarcomas, these tumors are difficult to diagnose, have high rates of recurrence, and frequently develop resistance to current treatment options. The challenges involving the management of these tumors arise from the fact that the molecular mechanisms governing their progression have not been entirely elucidated. Hence, to fill this gap and highlight the importance of ongoing and future studies, we have cross-referenced the literature on uterine LMS and ESS and compiled the most relevant epigenetic studies, published between 2009 and 2022.

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A Pan-Cancer Landscape Analysis Reveals a Subset of Endometrial Stromal and Pediatric Tumors Defined by Internal Tandem Duplications of BCOR

Cited by 37 publications

References 14 publications

Paediatric BCOR‐associated sarcomas with a novel long spliced internal tandem duplication of BCOR exon 15

Paediatric BCOR‐associated sarcomas with a novel long spliced internal tandem duplication of BCOR exon 15

High-Grade Endometrial Stromal Sarcoma: Molecular Alterations and Potential Immunotherapeutic Strategies

Epigenetic Features in Uterine Leiomyosarcoma and Endometrial Stromal Sarcomas: An Overview of the Literature

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